Synergistic Protection by Isoquercitrin and Quercetin against Glutamate-Induced Oxidative Cell Death in HT22 Cells via Activating Nrf2 and HO-1 Signaling Pathway: Neuroprotective Principles and Mechanisms of Dendropanax morbifera Leaves

Abstract

Dendropanax morbifera leaves (DML) have long been used as traditional medicine to treat diverse symptoms in Korea. Ethyl acetate-soluble extracts of DML (DMLE) rescued HT22 mouse hippocampal neuronal cells from glutamate (Glu)-induced oxidative cell death; however, the protective compounds and mechanisms remain unknown. Here, we aimed to identify the neuroprotective ingredients and mechanisms of DMLE in the Glu-HT22 cell model. Five antioxidant compounds were isolated from DMLE and characterized as chlorogenic acid, hyperoside, isoquercitrin, quercetin, and rutin by spectroscopic methods. Isoquercitrin and quercetin significantly inhibited Glu-induced oxidative cell death by restoring intracellular reactive oxygen species (ROS) levels and mitochondrial superoxide generation, Ca2+ dysregulation, mitochondrial dysfunction, and nuclear translocation of apoptosis-inducing factor. These two compounds significantly increased the expression levels of nuclear factor erythroid-2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) in the presence or absence of Glu treatment. Combinatorial treatment of the five compounds based on the equivalent concentrations in DMLE showed that significant protection was found only in the cells cotreated with isoquercitrin and quercetin, both of whom showed prominent synergism, as assessed by drug–drug interaction analysis. These findings suggest that isoquercitrin and quercetin are the active principles representing the protective effects of DMLE, and these effects were mediated by the Nrf2/HO-1 pathway.

Neuroprotective Properties of Kempferol Derivatives from Maesa membranacea against Oxidative Stress-Induced Cell Damage: An Association with Cathepsin D Inhibition and PI3K/Akt Activation

“…A growing body of research suggests that flavonols are not only active as neuroprotectants in in vitro experimental conditions but are effective in vivo in attenuating deficits in CNS function caused by ischemia, intoxication or age-related dementia and cognitive impairment [ 33 , 34 , 35 , 36 , 37 ]. Isoquercitrin (IQ), used as a reference compound in our study, at the concentration of 100 µM, diminished glutamate-induced toxicity in HT22 hippocampal cells [ 38 , 39 ] and protected rat pheochromocytoma cells (PC12) against 6-OHDA-induced oxidative stress [ 40 ], which is consistent with our findings where IQ (50 µM) attenuated cell damage induced by these oxidative stress inducers in human neuroblastoma SH-SY5Y cells. In vivo, the compound demonstrated neuroprotective activity in diabetic neuropathy [ 41 ] and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced acute mouse models of Parkinson’s disease [ 42 ].…”

Hyperoside and Quercitrin in Houttuynia cordata Extract Attenuate UVB-Induced Human Keratinocyte Cell Damage and Oxidative Stress via Modulation of MAPKs and Akt Signaling Pathway

“…The best characterized mechanism of antioxidant action of flavonoids is due to their ability to interact with ROS by scavenging or reducing them. From the previous studies, the ethyl acetate fraction of H. cordata , hyperoside, and quercitrin exhibited high reducing capacities [ 35 , 47 , 48 ]. The reduction property of the substance has a close correlation with its antioxidant capacity by donating electron or a hydrogen atom.…”

Rhinacanthin-C but Not -D Extracted from Rhinacanthus nasutus (L.) Kurz Offers Neuroprotection via ERK, CHOP, and LC3B Pathways

“…The molecular mechanisms underlying the death of HT-22 cells subjected to glutamate have been debated, mainly because the features of cell death manifest as both apoptotic and non-apoptotic [ 38 , 39 , 40 ]; furthermore, treatment with caspase inhibitors has provided mixed results, with some studies finding them to be protective [ 41 , 42 ]. In contrast, some others find them ineffective.…”